Obesity and Gut’s Dysbiosis Promote Neuroinflammation, Cognitive Impairment, and Vulnerability to Alzheimer’s disease: New Directions and Therapeutic Implications

Abstract

Obesity, an epidemic problem in the world is associated with several health problems. An understanding of mechanisms/factors that predispose, delay or protect individuals from obesity and its associated metabolic disturbances and cognitive impairment would be invaluable. The human gut harbors a diverse population of microbial organisms which are symbiotic and important for well being. However, studies on conventional and germ-free animals have shown that alteration in normal commensal gut microbiota and an increase in pathogenic microbiome (termed “dysbiosis”) contribute to gut inflammation, generation of LPS and pro-inflammatory cytokines, gut leakage, and systemic- and neuro-inflammation. The immune mechanisms that are necessary for gut homeostasis may become dysfunctional and lead to bowel inflammation and gut-brain axis dysfunction. These factors are potentially involved in inducing obesity as well. It may be wise to consider the wider hypothesis that gut’s dysbiosis, commencing as a response to fatty food, modulates neuro-inflammation and cognitive dysfunction. This may be enhanced by concomitant noxious factors such as consumption of NSAIDS and alcohol in the elderly. The neurotoxic mechanisms when chronic may enhance vulnerability to dementia of Alzheimer’s type (AD), and perhaps contribute to other dementias as well. Therapeutic strategies for amelioration of cognitive decline and AD are desperately needed. It is pragmatic then that immunologically mediated gut dyshomeostasis is abrogated by available options including Prebiotics, Probiotics, and Synbiotics. Decreasing gut’s dysbiosis may thus attenuate neuroinflammation and provide a potential treatment for obesity-related cognitive impairment. Further, the 'gut-brain axis' or 'brain-gut axis' (depending on whether one considers bottom-up or top-down pathway) is a bi-directional communication system, comprised of neural pathways encompassing enteric nervous system and the vagus. Vagus nerve stimulation in conjunction with α7 nAChR agonists may be an important therapeutic modality in gut pathology to upregulate parasympathetic/vagal efferent function, ameliorate gut-brain axis dysfunction and neuroinflammation, and decrease vulnerability to AD.